1-alkyl-1h,4h-pyrido(2,3-d)(1,3)oxazine-2,4-diones and their conversion to 1-alkyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids

ABSTRACT

1-R1-7-Q - 1H,4H - PYRIDO(2,3-D)(1,3)OXAZINE - 2,4DONE (I) WHERE R1 IS LOWER-ALKYL AND Q IS LOWER-ALKYL, LOWER-ALKANOYLOXYMETHYL, 4-(OR 3)-PYRIDYL OR 4(OR 3)PYRIDYL HAVING ONE OR TWO LOWER-ALKYL SUBSTITUENTS; THE PREPARATION OF I BY HEATING 2-R1NH-6-O&#34;-NICOTINIC ACID (V) WITH A LOWER-ALKYL CHLOROFORMATE OR PHOSGENE TO PREPARE I WHERE Q IS Q&#34;, WHICH IS LIKE Q BUT EXCLUDING LOWER-ALKANOYLOXYMETHYL, OR BY CONVERTING I WHERE Q IS CH3 TO ITS 8-OXIDE AND REACTING THE OXIDE WITH A LOWERALKANOIC ACID ANHYDRIDE TO PRODUCE I WHERE Q IS LOWERALKANOYLOXYMETHYL; THE CONVERSION OF I TO LOWER-ALKYL 1-R1-2-R2-1,4-DIHYDRO-4-OXO-7-Q-1,8-NAPHTHYRIDINE3-CARBOXYLATE (III) BY REACTING I WITH   R2-C(=O)CH2COOR,   WHERE R2 IS H OR CH3 AND R IS LOWER-ALKYL; AND, THE HYDROLYSIS OF III TO PRODUCE 1-R1-2-R2-1,4-DIHYDRO-4-OXO7-Q&#39;&#39;-1,8-NAPHTHYRIDINE-23:CARBOXYLIC ACID (IV), WHERE Q&#39;&#39; IS LIKE Q BUT HAVING HYDROXYMETHYL INSTEAD OF LOWER-ALKANOYLOXYMETHYL. ALSO SHOWN ARE: THE HYDROLYSIS OF 1,2-DIHYDRO-2-OXO-6-Q&#34;&#39;&#39;-NICOTINONITRILE (VII), WHERE Q&#34;&#39;&#39; IS 4(OR 3)-PYRIDYL OR 4(OR 3)-PYRIDYL HAVING ONE OR TWO LOWER-ALKYL SUBSTITUENTS, TO PRODUCE 1,2-DIHYDRO-2OXO-6-Q&#34;&#39;&#39;-NICOTINIC ACID (VIII); THE HALOGENATION OF VIII TO PRODUCE 2-HALO-6-Q&#34;&#39;&#39;-NICOTINIC ACID (VI&#39;&#39;); AND, THE REACTION OF VI&#39;&#39; WITH R1NH2 TO PRODUCE 2-R1NH-6-Q&#34;&#39;&#39;NICOTINIC ACID.

United States Patent l-ALKYL 1H,4H PYRIDO[2,3-d][1,3]0XAZINE-2,4- DIONESAND THEIR CONVERSION TO l-ALKYL- 1,4-DIHYDRO-4-0XO 1,8 NAPYRIDINE-S-CARBOXYLIC ACIDS Andrew W. Zalay, Albany, and Malcolm R. Bell, EastGreenbush, N.Y., assignors to Sterling Drug Inc., New York, N.Y.

No Drawing. Continuation-impart of abandoned application Ser. No.312,825, Dec. 7, 1972. This application Mar. 29, 1973, Ser. No. 346,191

Int. Cl. C07d 31/36, 87/20 U.S. Cl. 260-244 R 9 Claims ABSTRACT OF THEDISCLOSURE 1-R -7-Q 1H,4H pyrido[2,3-d][1,3]oxazine 2,4- dione (I) whereR is lower-alkyl and Q is loWer-alkyl, lower-alkanoyloxymethyl, 4(or3)-pyridyl or 4(or 3)- pyridyl having one or two lower-alkylsubstituents; the preparation of I by heating 2-R NH-6-Q-nicotinic acid(V) with a lower-alkyl chloroformate or phosgene to prepare I where Q isQ", which is like Q but excluding lower-alkanoyloxymethyl, or byconverting I where Q is CH to its 8-oxide and reacting the oxide with aloweralkanoic acid anhydride to produce I where Q isloweralkanoyloxymethyl; the conversion of I to lower-alkyl 1-R -2-R 1,4dihydro 4 oxo-7-Q-1,8-naphthyridine 3-carboxylate (III) by reacting Iwith where R is H or CH and R is lower-alkyl; and, the hydrolysis of IIIto produce 1-R -2-R -1,4-dihydro-4-oxo- 7-Q 1,8 naphthyridine 3carboxylic acid (IV), where Q is like Q but having hydroxymethyl insteadof lower-alkanoyloxymethyl. Also shown are: the hydrolysis of1,2-dihydro-2-oxo-6-Q"'-nicotinonitrile (VII), where Q" is 4(or3)-pyridyl or 4(or 3)-pyridy1 having one or two lower-alkylsubstituents, to produce 1,2-dihydro-2- oxo-6-Q"-nicotinic acid (VIII);the halogenation of VIII to produce 2-halo-6-Q-nicotinic acid (VI');and, the reaction of V1 with R NH to produce 2-R NH-6-Q- nicotinic acid.

This application is a continuation-in-part of copending application Ser.No. 312,825, filed Dec. 7, 1972 and now abandoned.

This invention relates to a process for producing 4-oxo- 1,8naphthyridine 3 carboxylic acid derivatives and to intermediates usedtherein.

The invention provides a novel process which comprises reacting 1-R -7-Q1H,4H pyrido[2,3-d] [1,3]oxazine- 2,4-dione of formula I with a compoundof formula II 0 R -b-OH -COOR II where Q is lower-alkyl,lower-alkanoyloxymethyl, 4(or 3)- pyridyl or 4(or 3)-pyridyl having oneor two loWer-alkyl substituents, R and R are each lower-alkyl and R is Hor CH to produce loWer-alkyl 1-R 1,4 dihydro-2-R 4 oxo 7 Q 1,8naphthyridine 3 carboxylate of formula III N ii III where Q, R, R and Rare defined as above for formulas I and II, and hydrolyzing III toobtain the corresponding 3-carboxylic acid of formula IV where Q islower-alkyl, hydroxymethyl, 4(or 3)-pyridyl or 4(or 3)-pyridyl havingone or two lower-alkyl substituents, R is lower-alkyl and R is H or CHThe com pounds of formula IV are disclosed and claimed in US. Pat.3,590,036, issued June 29, 1971. Perhaps best known COOR because oftheir high antibacterial activity are nalidixic iCOOH Q \N NHR with alower-alkyl chloroformate or phosgene, where R is defined as in formulaI and Q" is lower-alkyl, 4(or 3)- pyridyl or 4(or 3)-pyridyl having oneor two lower-alkyl substituents, which, in turn, are prepared byreacting the corresponding 2 halo-6-Q-nicotinic acid (VI) with alower-alkylamine of the formula R NH and in the process for thepreparation of I where Q is loweralkanoyloxymethyl which comprisesreacting 1-R -7- methyl 1H,4H pyrido[2,3-d] [1,3]oXazine-2,3-dione (Iwhere Q is methyl) with an oxidizing agent capable of convertingpyridines to pyridine-N-oxides to produce 1-R 7 methyl 1H,4Hpyrido[2,3-d] [1,3]oxazine-2,4-dione- 8-oxide and then reacting said8-oxide with a loweralkanoic acid anhydride to produce I where Q isloweralkanoyloxymethyl.

Disclosed and claimed in the copending Brundage and Lesher applicationSer. No. 346,190, filed (even date herewith), is the intermediate 2-RNH-6-Q"-nicotinic acid of formula V COOH where R is lower-alkyl and Q is4(or 3)-pyridyl or 4(or 3)-pyridyl having one or two lower-alkylsubstituents, and in the process of its preparation which comprises thecombination of the three steps of hydrolyzing 1,2-dihydro 2oxo-6-Q"-nicotinonitrile (VII) to produce1,2-dihydro-2-oXo-6-Q-nicotinic acid (VIII), halo- 3 genating VIII toproduce 2-halo-6-Q"-nicotinic acid (VI') and reacting V1 with alower-alkylamine of the formula R NH to produce V. In addition to saidcombination of the three steps, other process aspects of the inventionare each individual step and the two combinations of two consecutivesteps.

Also disclosed and claimed in said copending application Ser. No.346,180 are the compounds: 1,2-dihydro-2- oxo-6-Q-nicotinic acid and itst-automeric 2-hydroxy-6- Q-nicotinic acid of the respective formulasVIII and VHIA VIII VIIIA and, also, 2-halo-6-Q-nicotinic acid of theformula VI COOH where Q" has the meaning designated hereinabove forformula V and X is halo, preferably chloro or bromo.

Because of the ready availability and/or low cost of intermediatesand/or because of high antibacterial activity of the final products (IIIor IV), preferred process and composition embodiments of the variousaspects of the inventions herein disclosed are those where R, is ethyl,R is hydrogen, halo is chloro, Q is methyl, acetoxymethyl, 4(or3)-pyridyl, 2-methyl-4-pyridyl or 2,6- dimethy1-4-pyridyl, Q is as Q andalso hydroxymethyl, Q" is as Q but excluding acetoxymethyl, and Q is4(or 3)-pyridyl, 2-methyl-4-pyridyl or 2,6-dimethyl-4-pyridyl.

The term lower-alkyl, as used herein, e.g., as represented by R informula I, III or IV or as a substituent of 4(or 3)-pyridyl whenrepresented by Q in formula I or III or by Q in formula IV, means alkylradicals having from one to six carbon atoms which can be arranged asstraight or branched chains, illustrated by methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl, n-amyl, n-hexyl, and the like.

The term lower-alkanoyl, as used herein, e.g., in the definition of theQ substituent as 'lower-alkanoyloxymethyl in formula I or III, meansalkanoyl radicals having from one to six carbon atoms, including thestraightand branched-chain radicals, illustrated by formyl, acetyl,prop-ionyl (propanoyl), butyryl (butanoyl), isobutyryl(Z-methylpropanoyl) and caproyl (hexanoyl).

Illustrative of the Q substituent in formula I or III or of the Qsubstituent in formula IV or of the Q" substituent in formula V or ofthe Q substituent in formula V, VI, VII, VIII or VIIIA where Q or Q orQ" or Q, respectively, is 4(or 3)-pyridyl having one or two lower--alkyl substituents are the following: 2-methyl-4-pyridyl,2,6-dimethyl-4-pyridyl, 3-methyl-4-pyridyl, 2-methyl 3- pyridyl,6-methyl-3-pyridy1 (preferably named Z-methyl- 5-pyridyl), 2,3-dimethyl5 pyridyl, 2,5 dimethyl-4- pyridyl, 2-ethyl-4-pyridyl, 2-isopropyl 4pyridyl, 2-nbutyl-4-pyridyl, 2-n-hexyl-4-pyridyl, 2,6-diethyl-4-pyridyl,2,6-diethyl-3-pyridyl, 2,6-diisopropyl-4-pyridyl,2,6-di-nhexyl-4-pyridyl, and the like.

As shown above, 1,2 dihydro 2 oxo-6-Q"-nicotinic acid of formula VIII istautomeric with 2-hydroxy-6-Q'- nicotinic acid of formula VIIIA. As withall tautomeric systems, the rate of the transformation VIII VIIIA andthe ratio VIII/VHIA are dependent on the thermodynamic environment,including the state of aggregation; so that measurements by anyparticular techniques do not necessarily have validity except under theconditions of the measurement, thereby, among other consequences, givingrise to problems for any simple designation of the physical embodiments.Thus, measurements of the infrared spectra, in potassium bromideadmixture, or in chloroform or mineral oil, indicate existencepredominantly as VIII and the names of the compounds herein thereforeare preferably based on structure VIII, although it is understood thateither or both structures are comprehended.

The intermediate Z-(lower-alkylamino) 6 (loweralkyl)-nicotinic acid (Vwhere Q" is lower-alkyl) is prepared by halogenating the generally known1,2-dihydro- 2-oxo-6-(lower-alkyl)nicotinic acid with a halogenatingagent, preferably a chlorinating agent, e.g., PCl PCl P001 SO Cl and thelike, to produce 2-halo-6-(loweralkyl)-nicotinic acid and then reactingsaid 2-halo acid with a lower-alkylamine (R N-H The generally knownintermediate 1,2-dihydro-2-oxo- 6-Q-nicotinonitrile (VII) or tautomer(VIIA) is prepared by the known procedure of first reacting 4(or 3)-acetylpyridine or 4(or 3)-acetylpyridine substituted on the pyridinering by one or two lower-alkyl substituents, as represented by Q-COCHwith ethyl formate and sodium methoxide to yield the sodium salt of Q"-COCH CHO, e.g., the sodium salt of isonicotinoylacetaldehyde where Q' is4-pyridyl, and then reacting said sodium salt with cyanoacetamide inaqueous medium to produce said 1,2-dihydro-2-oxo-6 Q' nicotinonitrile,e.g., where Q' is 4-pyridyl, also named 1,6-dihydro-6-oxo[2,4'-bipyridine]-5-carbonitrile.

The molecular structures of said intermediate aspects (I, V, VI, VIIIand VIIIA) of the inventions herein disclosed and of the final products(III and IV) are assigned on the basis of evidence provided by infrared,ultraviolet and nuclear magnetic resonance spectra, and by thecorrespondence of calculated and found values for the elementaryanalysis for representative examples.

The manner of making and using the instant invention will now begenerally described so as to enable a person skilled in the art ofpharmaceutical chemistry to make and use the same, as follows:

The hydrolysis of 1,2-dihydro-2-oxo-6-Q"-nicotinonitrile (VII) or itstautomer (VIIA) to produce the corresponding1,2-dihydro-2-oxo-6-Q"-nicotinic acid is preferably carried out byrefluxing VII (or VIIA) in an aqueous acidic medium, preferably usingfrom about 1:2 to 1:1 parts by volume of concentrated (-97%) sulfuricacid and water, respectively. Other aqueous acidic media can be used,e.g., 6N hydrochloric acid, and the like.

The reaction of 1,2-dihydro-2-oxo 6 -'(lower alkyl)- nicotinic acid(VIII) or 2-hydrox'y-6-Q'"-nicotinic acid (VIIIA) with a halogenatingagent, preferably a mixture of phosphorus oxychloride and phosphoruspentachloride, is carried out by heating the reactants, preferably atabout 50l10 C. The reaction is conveniently run by refluxing thereactants in chloroform; however, the reaction can be run in the absenceof a solvent or using another inert solvent, e.g., benzene, toluene,xylene, chlorobenzene, methylene dichloride, and the like. Also, otherchlorinating agents can be used, e.g., phosphorous oxychloride orphosphorus pentachloride alone, phos phorus trichloride, thionylchloride, phosgene, phenylphosphonic dichloride, and the like.

The reaction of 2-halo-6-Q (or Q') -nicotinic acid (VI or VI) with alower-alkylamine, R -NH to produce 2-R NH-6-Q (or Q)-nicotinic acid (Vor V) is conveniently carried out by heating the reactants together in astainless steel autoclave. The reaction temperature is about 75150 C.,preferably about 90-1l0 C. Alternatively, a suitable inert solvent canbe used, e.g., ethanol, toluene, xylene, benzene, and the like.

The reaction of 2-R NH-6-Q"-nicotinic acid (V) With a lower-alkylchloroformate to produce 1-R -7-Q"- 1H,4H- pyrido[2,3-d][1,3]oxazine-2,4-dione is carried out by heating the reactants at about-175 0., preferably about -150 C. in the absence or presence of an inertsolvent, e.g., xylene. Alternatively, phosgene can be used in place ofthe lower-alkyl chloroformate.

The reaction of 1-R -7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,3-dione (I where Q is methyl) with an oxidizing agent toproduce 1-R -7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxzine-2,4-dione-8-oxideis carried out by reacting I where Q is methyl with an oxidizing agentcapable of converting pyridines to pyridine-N-oxides, preferably with aper acid, e.g., peracetic acid, perbenzoic acid, 3-chloroperbenzoicacid, and the like, or with other oxidizing agents, e.g., hydrogenperoxide, in the presence of a suitable solvent inert under the reactionconditions, e.g., acetic acid, chloroform, and the like. The reaction isconveniently run by mixing the reactants carefully at room temperature(about 25 C.) up to about 4050 C., preferably with stirring, and thenheating the reaction mixture on a steam bath to ensure completion of thereaction.

The conversion of l-R -7methyl-lH,4H-pyrido[2,3-d][1,3]oxazine-2,3-dione-8-oxide to 1-R -7-(lower-alkanoyloxymethyl)-lH,4H-pyrido [2,3-d] [1,3]oxazine-2,3-dion is carried out byreacting said 8-oxide with a lower-alkanoic acid anhydride. The reactionis conveniently run using as solvent an excess of the anhydride or thecorresponding alkanoic acid, e.g., acetic acid with acetic anhydride, orany suitable solvent unreactive to said anhydrides, e.g., acetonitrile,benzene, toluene, dimethylformamide, and the like. The reaction isgenerally carried out in the range of about 70-150 C., preferably on asteam bath.

The reaction of 1-R -7-QlH,4H-pyrido[2,3-d] [1,3] oxazine-2,4-dione (I)with a lower-alkyl acetoacetate (II, R =CH or formylacetate (II, R =H),the latter preferably as its alkali metal enolate, to produce aloWer-alkyl 1R -1,4-dihydro-4-oxo-2R -7-Q-1,8 naphthyridine 3-carboxylate (III) is carried out by heating the reactants in thev rangeof about 50-150 C., preferably about EEO-120 C., preferably using aninert solvent, e.g., dimethylformamide. Alternatively, the lower-alkylformylacetate can be prepared in situ from a lower-alkyl ether orloweralkanoate (1-6 carbon atoms) of its enol form, preferably itsmethyl or ethyl ether or its acetate.

The hydrolysis of lower-alkyl 1-R -l,4-dihydro-4-oxo- 2-R-7-Q-l,'8-naphthyridine-3-carboxylate (III) to produce 1-R-1,4-dihydro-4-oxo-2-R -7-Q'-1,8 naphthyridine 3- carboxylic acid (IV)is run either under acidic or alkaline conditions. The hydrolysis can becarried out from about room temperature C.) to about 100 C. using, wherenecessary, an appropriate solvent, e.g., water, ethanol, methanol,acetone, and the like. Various acidic or alkaline solutions can be used,e.g., aqueous hydrochloric acid, hydrobromic acid, sulfuric acid, sodiumhydroxide, potas sium hydroxide, calcium hydroxide, and the like.

The best mode contemplated for carrying out the invention is now setforth as follows:

Example 1 2-Chloro-6-methylnicotinic acid.To a mixture of 75 ml. ofphosphorus oxychloride, 340 g. of finely ground phosphorus pentachlorideand 800 ml. of chloroform was added 123 g. of well ground powdered1,2-dihydro-6- methyl-Z-oxonicotinic acid whereupon a slightlyexothermic reaction ensued. This reaction mixture was heated to boilingover a period of one hour and then was refluxed for eight and one-halfhours. The reaction mixture was next concentrated in vacuo and thenconcentrated in vacuo at 0.5 mm. after diluting it with methylenedichloride. The resulting residual brown oil containing some solid waspoured into 800 ml. of ice water and the resulting mixture stirred atroom temperature for three hours. A brown granular precipitate wasfiltered off and washed with three 60 ml. portions of water. Thecombined aqueous filtrate and washings were extracted with two 500 ml.portions of chloroform. Said brown granular precipitate Was extractedwith the same chloroform and then extracted with a third 500 ml. portionof boiling chloro-' form. The combined chloroform extracts were washedwith water, dried over anhydrous magnesium sulfate, treated withdecolorizing charcoal, filtered and concentrated in vacuo to remove thesolvent. The crystalline residue was recrystallized from ethyl acetateand dried in vacuo at 60 C. for two hours to yield a first crop of 44g., m.p. 142-l49 C., and a second crop of 20 g., m.p. 138-143 C.Recrystallization of these two crops plus 7 g. of product obtained byanother run from 300 ml. of ethyl acetate gave 41.4 g. of2-chloro-6-methylnicotinic acid, mp. 150-151" C. Also obtained was asecond crop of 9.3 g., mp. 141-147 C. Using molar equivalent quantitiesof pohsphorus oxybromide and phosphorus pentabromide in place ofphosphorus oxychloride and phosphorus pentachloride, respectively,2-bromo-6-methylnicotinic acid is obtained.

Following the procedure described above in Example 1 but using in placeof l,2-dihydro-6-methyl-2-oxonicotinic acid a molar equivalent quantityof the appropriate corresponding 1,2-dihydro-6-(lower-alkyl)-2oxonicotinic acid, there are obtained the following2-chloro-6-(1oweralkyl)nicotinic acids: 2-chloro-6-ethylnicotinic acidusing 6-ethyl-l,2-dihydro-2-oxonicotinic acid;2-chloro-6-isopropylnicotinic acid using 1,2-dihydro-6-isopropyl-2-oxonicotinic acid; 6-n-butyl-2-chloronicotinic acid using6-n-butyl-l,Z-dihydro-Z-oxonicotinic acid; and 2-chloro-6-n-hexylnicotinic acid using 6-n-hexyl-1,2-dihydro-2-oxonicotinic acid.

Example 2 Z-Ethylamino-G-methylnicotinic acid.-A mixture of 41.4 g. of2-chloro-6-methylnicotinic acid and 520 ml. of 70% aqueous ethylaminewas heated in a stainless steel autoclave for twenty hours at C., themaximum pressure being about 200 lbs. per square inch. The reactionmixture was concentrated in vacuo. To the remaining brown oil was added20.3 g. of sodium bicarbonate in 270 ml. of water and the mixture wasconcentrated in vacuo. The resulting residue was taken up in benzene andthe solution concentrated in vacuo to remove the benzene; this benzenetreatment was repeated twice. The residue was dissolved in hot benzene,the solution filtered, and the filtrate concentrated to yield 49 g. ofcrude product, 2-ethylamino-6-methylnicotinic acid, which was used inExample 3 without further purification. In another run, the crudeproduct (from 10.89 of 2-chloro-6-methylnicotinic acid) wasrecrystallized once from benzene to yield the product as a ten-yellowsolid (9.8 g.), m.p. 112l15 C. A sample for analysis, mp. 116-118 C.,was obtained by recrystallization from benzene-cyclohexane aftertreating the hot benzene solution with decolorizing charcoal andfiltering off the charcoal.

Following the procedure described above in Example 2 but using in placeof 2-chloro-6-methylnicotinic acid or in place of aqueous ethylamine amolar equivalent quantity of the appropriate2-halo-6-(lower-alkyl)nicotinic acid or aqueous lower-alkylamine,respectively, there are obtained the following 2-(lower-alkylamino)-6-(lower-alkyl)nicotinic acids: 6-ethyl-Z-ethylaminonicotinic acid using2-chloro-6-ethylnicotinic acid, 2-ethylamino-6-isopropylnicotinic acidusing 2-chloro-6-isopropylnicotinic acid;6-n-butyl-2-ethylaminonicotinic acid using 2-chloro-S-n-butylnicotinicacid; 2-ethylamino-6-nhexylnicotinic acid using2-chloro-6-n-hexylnicotinic acid; 6-methyl-Z-methylaminonicotinic acidusing aqueous methylamine; 6-methyl-2-n-propylaminonicotinic acid usingaqueous n-propylamine; 2-isobutylamino-6-methylnicotinic acid usingaqueous isobutylamine; and 2-nhexylamino-6-methylnicotinic acid usingaqueous n-hexylamine.

Example 3 1-Ethyl-7-methyl- 1H, 4H-pyrido [2,3-d] [1,3 oxazine-2,4-dione.-To a solution containing 49 g. of 2-ethylamino-6- methylnicotinicacid dissolved in 250 ml. of Xylene, was added 400 ml. of ethylchloroformate and the mixture was refluxed for twenty hours. Thereaction mixture was concentrated in vacuo, the residue taken up inbenzene and the benzene removed in vacuo. The benzene treatment wasrepeated. The residue was crystallized from benzene-cyclohexane to yield29 g. of crystalline product, which had a faint odor of ethylchloroformate. The product was triturated twice with etherzcyclohexane(121), the mixture filtered and the product dried in. vacuo for twohours to yield 28.7 g. of 1-ethyl-7-methyl-1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione, m.p. 116l17 C.

Alternatively, the above preparation can be carried out using phosgenein place of ethyl chloroformate.

Example 4 l-Ethyl-1,4-dihydro 2,7dimethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid-To a cooled andstirred mixture containing 70 ml. of dry dimethylformamide and 4.4 g. ofsodium hydride (60%) under an atmosphere of nitrogen was added withstirring 14 ml. of ethyl acetoacetate. After the foaming had subsided(about thirty minutes), to the stirred mixture was added 22.7 g. oflethyl-7-methyl 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4- dione and theresulting stirred reaction mixture was slowly warmed up to 90 C. (on asteam bath) and kept there for six hours. The reaction mixture was thenconcentrated in vacuo to yield 37 g. of brown gummy residue containingethyl l-ethyl-l,4-dihydro-2,7-dimethyl-4-oxo-1,8-naphthyridine-3-carboxylate. The residue was dissolved in 250ml. of 95% ethanol; 36.8 ml. of 35% aqueous sodium hydroxide solutionwas added; and the mixture was refluxed with stirring for two hours. Thehot reaction mixture was filtered and the filtrate concentrated invacuo. The residual solid was dissolved in 280 ml. of Water, thesolution filtered and the filtrate acidified with acetic acid plus somehydrochloric acid to a pH or 5. The acidic solution was cooled and theseparated product was collected to yield 16.35 g. of tan-white crystalsafter drying in vacuo at 90 C. The crystals were recrystallized oncefrom tetrahydrofuran-benzene and them twice from tetrahydrofuran toyield, as white crystals, 7.2 g. ofl-ethyl-l,4-dihydro-2,7-dimethyl-4-oxo-1,8- naphthyridine-3-carboxylicacid, m.p. 226227 C.

Example 5 1-Ethyl-l,4-dihydro 7methyl-4-oxo-LS-naphthyridine-3-carboxylic acid is prepared followingthe procedure described in Example 4 but using in place of ethylacetoacetate an equivalent molar quantity of ethyl formylacetate.

Following the procedure described in Example 3 but using in place of2-ethylamino-6-methylnicotinic acid a molar equivalent quantity of theappropriate 2-(loweralkylarnino)-6-(lower-alkyl)nicotinic acid, thefollowing l-(lower-alkyl)-7-(lower-alkyl) lH,4I-l pyrido[2,3-d][l,3]oxazine-2,4-diones of Examples 6-l3 are prepared:

Example 6 1,7-Diethyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4- dione using2-ethylamino-6-ethylnicotinic acid.

Example 7 1-Ethyl-7-isopropyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dio11eusing 2 ethylamino-6-isopropylnicotinic acid.

Example 8 7-n-Butyl-l-ethyl 1H,4H pyrido[2,3-d] [l,3]oxazine- 2,4-dioneusing 6-n-butyl-2-ethylaminonicotinic acid.

Example 9 l-Ethyl-7-n-hexyl 1H,4H pyrido[2,3d] [l,3]oxazine using2-ethylamin0-6-n-hexylnicotinic acid.

Example 10 1,7-Dimethyl 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4- dioneusing 6-methyl-2-methylaminonicotinic acid.

8 Example 11 7-Methyl-l-n-propyl 1H,4H pyrido[2,3 d][l,3]oxazine-2,4-dione using 6-methyl-2-n-propylaminonicotinic acid.

Example 12 1-Isobutyl-7-methyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dioneusing 2-isobuty1amino-6-methylnicotinic acid.

Example 13 l-n-Hexyl-7-methyl lH,4H pyrido[2,3-d] [1,3]oxazine-2,4-dioneusing 2-n-hexylarnino-o-methylnicotinic acid.

Following the procedure described in Example 4 but using in place of1-ethyl-7-methyl-1H,4H-pyrido[2,3-d] [l,3]oxazine-2,4-dione and/or ethylacetoacetate molar equivalent quantities, respectively, of theappropriate 1- (lower alkyl) 7 (lower-alkyl)-lH,4I-l-pyrido[2,3-][l,3]oxazine-2,4-dione and/or ethyl formylacetate, there are obtainedthe compounds of Examples 14-21:

Example 14 1,7-Diethyl-l,4-dihydro 4 oxo-1,8-naphthyridine-3- carboxylicacid using 1,7-diethyl-1H,4H-pyrid0[2,3-d] [1,3]oxazine-2,4-dione andethyl formylacetate.

Example 15 1-Ethyl-7-isopropyl 1,4 dihydro-l,8-naphthyridine-B-carboxylic acid using l-ethyl-7-isopropyl-lH,4H-pyrido [2,3-d][1,3]oxazine-2,4-dione and ethyl formylacetate.

Example 16 7-n-Butyl-l-ethyl 1,4 dihydro-2-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid using 7-n-butyl-1-ethyl-1H,4H-pyrido[2,3-d][1,3]0xazine-2,4-dione and ethyl acetoacetate.

Example 17 1-Ethyl-7-n-hexyl-1,4-dihydro 2 methyl-4-oxo-l,8naphthyridine-3-carboxylic acid using 1-ethy1-7-n-hexyl-1H,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione and ethyl acetoacetate.

Example 18 l,4-Dihydro-1,7-dimethyl 4 oxo-l,8-naphthyridine-3-carboxylic acid using 1,7-dimethyl-1H,4H-pyrido[2,3-d][l,3]oxazine-2,4-dione and ethyl formylacetate.

Example 19 1,4-Dihydro-7-methyl 4 oxo-1-n-propyl-4-oxo-1,8-naphthyridine-3-carboxylic acid using 7-methyl-l-n-propyl-1H,4H-pyrido[2,3-d] [l,3]oxazine-2,4-dione and ethyl formylacetate.

Example 20 1,4-Dihydro-1-isobutyl 2,7 dimethyl 4 oxo-1,8-naphthyridine-3-carboxylic acid using l-isobutyl-7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,4-dione and ethyl acetoacetate.

Example 21 1,4-Dihydro-l-n-hexyl 2,7 dimethyl 4 oxo-1,8-naphthyridine-3-carboxylic acid using 1-n-hexyl-7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine 2,4 dione and ethyl acetoacetate.

Example 22 1,2-Dihydro-6-(2-methyl-4-pyridyl)-2-oxonicotinic acid using1,2 dihydro-6 (2-methyl-4-pyridyl)-2-oxonicotinonitrilc, the latterprepared by reacting the sodium salt ofZ-methylisonicotinoylacetaldehyde with cyanoaceta-' mide.

Example 25 1,2-Dihydro-6-(3-methyl-4-pyridyl)-2-oxonicotinic acid using1,2 dihydro-6 (3-methyl-4-pyridyl)-2-oxonicotinonitrile, the latterprepared by reacting the sodium salt of3-methylisonicotinoylacetaldehyde with cyanocetamide.

i Example 26 6 (2-Ethyl-4-pyridyl)-l,2-dihydro-2-oxonicotinic acid using6-(2-ethyl-4-pyridyl) 1,2-dihydro-2-oxonicotinonitrile, the latterprepared by reacting the sodium salt of Z-ethylisonicotinoylacetaldehydewith cyanoacetamide.

Example 27 6 (3-Ethyl-4-pyridyl)-1,2-dihydro-2-oxonicotinic acid using6-(3-ethyl-4-pyridyl) 1,2-dihydro-Z-oxonicotinonitrile, the latterprepared by reacting the sodium salt of 3-ethylisonicotinoylacetaldehyde with cyanoacetamide.

Example 28 1,2 Dihydro-6-(2,6-dimethyl-4-pyridyl)-2-oxonicotinic acidusing 1,2 dihydro 6 (2,6-dimethyl-4-pyridyl)-2- oxonicotinonitrile, thelatter prepared by reacting the sodium salt of2,6-dimethylisonicotinoylacetaldehyde with v cyanoacetamide.

Example 29 1,2 Dihydro-6-(3,5-dimethyl-4-pyridyl)-2-oxonicotinic acidusing 1,2 dihydro 6 (3,5-dimethyl-4-pyridyl)-2- oxonicotinonitrile, thelatter prepared by reacting the sodium salt of3,5-dimethylisonicotinoylacetaldehyde with cyanoacetamide.

Following the procedure described in Example 1 but using in place of1,Z-dihydro-6-rnethyl-2-oxonicotinic acid a molar equivalent quantity ofthe appropriate 1,2dihydro-2-oxo-6-Q'-nicotinic acid, there are obtainedthe following 2-chloro-6-Q'-nicotinic acids of Examples 30- 37:

Example 30 2-Chloro-6-(3-pyridyl)nicotinic acid using 1,2-dihydro-2-oxo-6-(3-pyridyl)nicotinic acid.

Example 31 2 Chloro-6-(2 methyl-4-pyridyl)nicotinic acid using1,2-dihydro-6-(2-methyl-4-pyridyl)-2-0Xonic0tinic acid.

Example 32 2 Chloro-6 (3-methyl-4-pyridyl)nicotinic acid using1,2-dihydro-6-(3-methyl-4-pyridyl)-2-oxonicotinic acid.

Example 33 2-Chloro-6-(2-ethyl-4-pyridyl)nicotinic acid using 6-(2-ethyl-4-pyridyl)-1,2-dihydro-2-oxonicotinic acid.

Example 34 2-Chloro-6-(3-ethyl-4-pyridyl)nicotinic acid using 6-(3-ethyl-4-pyridyl)-l,2-dihydro-2-oxonicotinic acid.

Example 35 2-Chloro-6-(2,6-dimethyl-4-pyridyl)nicotinic acid using 1,2dihydro-6-(2,6-dimethyl-4-pyridyl) 2 oxonicotinic acid.

Example 36 2-Chloro-6-(4-pyridyl)nicotinic acid using 1,2-dihydro-2-oxo-6-(4-pyridyl)nicotinic acid.

Example 37 2-Chloro-6-(3,5-dimethyl-4-pyridyl)nicotinic acid using 1,2dihydro-6-(3,5-dimethyl-4-pyridyl) 2 oxonicotinic acid.

Following the procedure described in Example 2 but using in place of2-chloro-6-methylnicotinic acid or in place of aqueous ethylamine amolar equivalent quantity of the appropriate 2-halo-6-Q"'-nicotinic acidor aqueous lower-alkylamine, respectively, there are obtained thefollowing 2-(lower-alkylamino)-6Q'-nicotinic acids of Examples 3848:

Example 38 2 Ethylamino-6 (3 pyridyl)nicotinic acid using 2-chloro-6-(3-pyridyl)nicotinic acid and ethylamine.

Example 39 2 Ethylamino-6-(2-methyl-4-pyridyl)nicotinic acid using2-chloro-6-(2-methyl 4 pyridyl)nicotinic acid and ethylamine.

Example 40 2 Ethylamino-6-(3-methyl-4-pyridyl)nicotinic acid using2-chlor0-6-(3-methyl 4 pyridyl)nicotinic acid and ethylamine.

Example 41 2-Ethylamino-6-(2-ethyl-4-pyridyl)nicotinic acid using2-ch1oro-6 (2-ethyl-4-pyridyl)nicotinic acid and ethylamine.

Example 42 2-Ethylamino-6-(3-ethyl-4-pyridyl)nicotinic acid using 2chloro-6-(3-ethyl-4-pyridyl)nicotinic acid and ethylamine.

Example 43 2 Ethylamiuo-6-(2,6-dimethyl-4-pyridyl)nicotinic acid using 2chloro-6-(2,6-dimethyl-4-pyridyl)nicotiuic acid and ethylamine.

Example 44 2 Ethylamino-6-(3,5-dimethyl-4-pyridyl)nicotinic acid using 2chloro-6-(3,5-dimethyl-4-pyridyl)nicotinic acid and 'ethylamine.

Example 45 2 Methylamino-6- (4 pyridyl)nicotinic acid using 2-chloro-6-(4-pyridyl)nicotinic acid and methylamine.

Example 46 2-Isopropylamino-6-(2-methyl-4-pyridyl)nicotinic acid using2-chloro-6-(2 methyl-4-pyridyl)nicotinic acid and isopropylamine.

Example 47 2 n Butylamino-6-(4-pyridyl)nicotinic acid using 2-chloro6-(4-pyridyl)nicotinic acid and n-butylamine.

Example 48 2 n Hexylamino 6 (4 pyridyl)nicotinic acid using2-chloro-6-(4-pyridyl)nicotinic acid and n-hexylamine.

Example 49 2 Ethylamino 6 (4 pyridyl)nicotinic acid using 2- chloro-6-(l-pyridyl)nicotinic acid and ethylamine.

Following the procedure described in Example 3 but 1 1 using in place ofZ-ethylamino-6-methylnicotinic acid a molar equivalent quantity of theappropriate 2-(loweralkylamino)-6-Q'-nicotinic acid, there are obtainedthe following 1 (lower alkyl) 7-Q"-1H,4H-pyrido[2,3-d][1,3]oxazine-2,4-diones of Examples 50-61:

Example 50 1 Ethyl 7 (3 pyridyl) 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4-dione using 2-ethylamino-6-(3-pyridyl)nic0- tinic acid.

Example 51 l Ethyl 7 (2 methyl 4 pyridyl) 1H,4H pyrido-[2,3-d][1,3]oxazine-2,4-dione using 2-ethylamino-6-(2-methyl-4-pyridyl)nicotinic acid.

Example 52 1 Ethyl 7 (3 methyl 4 pyridyl) 1H,4H pyrido-[2,3-d][1,3]oxazine-2,4-dione using 2-ethylamino-6-(3- methyl-4-pyridyl)nicotinic acid.

Example 53 1 Ethyl 7 (2 ethyl 4 pyridyl) 1H,4H pyrido- [2,3-d] 1,3oxazine-2,4-dione using 2-ethylamino-6- (2- ethyl-4-pyridyl)nicotinicacid.

Example 54 1 Ethyl 7 (3 ethyl 4 pyridyl) 1H,4H pyrido[2,3-d][l,3]oxazine-2,4-dione using 2-ethylamino-6-(3-ethyl-4-pyridyl)nicotinic acid.

Example 55 1 Ethyl 7 (2,6 dimethyl 4 pyridyl) 1H,4Hpyrido[2,3-d][1,3]oxazine-2,4-dione using 2-ethylamino-6-(2,6-dimethyl-4-pyridyl)nicotinic acid.

Example 56 1 Ethyl 7 (3,5 dimethyl 4 pyridyl) 1H,4H- pyrid[2,3-d][1,3]oxazine 2,4-dione using Z-ethylamino-6-(3,5-dimethyl-4-pyridyl)nicotinic acid.

Example 57 1 Methyl 7 (4 pyridyl) 1H,4H pyrido[2,3-d][l,3]oxazine-2,4-dione using 2-methylamino-6-(4-pyridyl) nicotinic acid.

Example 58 1 Isopropyl 7 (2 methyl 4 pyridyl) 1H,4H-pyrido[2,3-d][1,3]oxazine-2,4dione using2-isopropylamino-6-(2-methyl-4-pyridyl)nicotinic acid.

Example 59 1 n Butyl 7 (4 pyridyl) 1H,4H pyridol[2,3-d][1,3]0xazine-2,4-di0ne using 2-n-butylamino-6-(4-pyridyl) nicotinicacid.

Example 60 1 n Hexyl 7 (4 pyridyl) 1H,4H pyrido[2,3-d] [1,310xazine 2,4dione using 2-n-hexylamino-7-(4-pyridyl) nicotinic acid.

Example 61 1 Ethyl 7 (4 pyridyl) 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione using 2-ethylamino-6-(4-pyridyl) nicotinic acid.

Following the procedure described in Example 4 but using in place of1-ethyl-7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,4-di0ne a molarequivalent quantity of the appropriate 1(lower-alkyl)-7-Q'-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,4-dione and eitherethyl acetoacetate or a molar equivalent quantity of ethylformylacetate, there are obtained thel-(lower-alkyl)-1,4-dihydro-2-methyl(0r 2-unsubstituted)-4-oxo-7-Q1,8naphthyridine 3 carboxylio acids of Examples 62-73:

Example 62 1- Ethyl 1,4 dihydro 4 0x0 7 (3 pyridyl)-1,8-naphthyridine-3-carboxylic acid using l-ethyl-7-(3-pyri- 1 2 dyl)-1H,4Hpyrido[2,3 d] [1,3]0xazine 2,4 dione and ethyl formylacetate.

Example 63 1 Ethyl 1,4 dihydro 7 (2 methyl 4 pyridyl)-4-oxo-1,8-naphthyridine-3-carb0xylic acid using l-ethyl-7(2-methyl-4-pyridyl)-1H,4H-pyrido[2,3 d] [1,3]0xazine- 2,4-dione andethyl formylacetate.

Example 64 1 Ethyl 1,4 dihydro 2 methyl 7 (3 methyl 4-pyridyl)-4-oxo-1,8-naphthyridine-3-carboxy1ic acid using 1 ethyl 7 (3methyl 4 pyridyl) 1H,4H pyrido- [2,3-d] [1,3]oxazine 2,4-dione and ethylacetoacetate.

Example 65 1 Ethyl 7 (2 ethyl 4 pyridyl) 1,4 dihydro 4-oxo-1,8-naphthyridine-3-carboxylic acid using 1-ethyl-7- (2 ethyl 4pyridyl) 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4-dione and ethylformylacetate.

Example 66 l Ethyl 7 (3 ethyl 4 pyridyl) 1,4 dihydro 2-methyl-4-oxo-l,8-naphthyridine-3-carboxylic acid using 1- ethyl 7 (3ethyl 4 pyridyl) 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4-dione and ethylacetoacetate.

Example 67 1 Ethyl 1,4 dihydro 7 (2,6 dimethyl 4pyridyl)-4-ox0-1,8-naphthyridine-3-carboxylic acid using 1- ethyl 7 (2,6dimethyl 4 pyridyl) 1H,4H pyrido [2,3-d] [l,3]oxazine-2,4-dionc andethyl formylacetate.

Example 68 1 Ethyl 1,4 dihydro 2 methyl 7 (3,5dimethyl-4-pyridyl)-4-0xo-1,8-naphthyridine 3 carboxylic acid using 1ethyl 7-(3,5-dimethyl-4-pyridyl)-1H,4H-pyrido[2,3-d][1,3]0xazine-2,4-dione and ethyl acetoacetate.

Example 69 1,4 Dihydro 1 methyl 4 oxo 7 (4 pyridyl)-l,8-naphthyridine-3-carboxylic acid using 1-methyl-7-(4-pyridyl)-1H,4H-pyrid0[2,3-d] [1,3]oxazine-2,4-dione and ethylformylacetate.

Example 70 1,4 Dihydro 1 isopropyl 7 (2 methyl 4pyridyl)-4-oxo1,8-naphthyridine-3-carboxylic acid using 1- isopropyl 7(2 methyl 4 pyridyl) 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4-dione andethyl formylacetate.

Example 71 1- n Butyl-1,4 dihydro 2 methyl 4 oxo 7 (4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using l-n-butyl 7 (4pyridyl) 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione and ethylacetoacetate.

Example 72 1- n Hexyl-1,4 dihydro 2 methyl- 4 0x0 7 (4-pyridyl)-1,8-naphthyridine-3-carboxylic acid using l-nhexyl 7 (4pyridyl) 1H,4H pyrido[2,3-d] [l,3]oxazine-2,4-dione and ethylacetoacetate.

Example 73 1 Ethyl 1,4 dihydro 4-oxo 7 (4 pyridyl) 1,8-naphthyridine-3-carboxylic acid using 1-ethyl-7- (4-pyridyl) 1H,4Hpyrido[2,3-d][1,3]0xazine-2,4-dione and ethyl formylacetate.

Example 74 1 Ethyl 7 methyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione-8-oxide.A mixture containing 20.6 g. of 1- ethyl7 methyl 1H,4H pyrido[2,3 d] [1,3]oxazine- 2,4-dione, 25 ml. ofperacetic acid and 250 ml. of acetic acid is heated with stirring forabout four hours on a steam bath. The reaction mixture is concentratedin vacuo until 7 Acetoxymethyl 1 ethyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione.A mixture containing 10.2 g. of 1 ethyl 7 methyl1H,4H pyrido[2,3 d] [1,3]oxa zine-2,4-dione-8-oxide, 5.5 g. of aceticanhydride and 35 ml. of acetic acid is heated with stirring on a steambath for fifty minutes and then evaporated in vacuo to dryness. Theresidue is crystallized from ethanol using decolorizing charcoal anddried in vacuo at 70 C. to yield 7-acetoxy methyl 1 ethyl 1H,4H pyrido[2,3 d] [1,3]oxazine- 2,4-dione.

Following the procedure described in Example 74 but using in place of1-ethyl-7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,4-dione a molarequivalent quantity of the appropriate l-(lower-alkyl) 7methyl-1H,4H-pyrido- [2,3-d] [1,3]oxazine 2,4 dione, there are obtainedthe corresponding l-(lower-alkyl) 7 methyl-lH,4H-pyrido-[2,3-d][1,3]oxazine-2,4-dione-8-oxides of Examples 76- 79:

Example 76 1,7-Dimethyl 1H,4H pyrido[2,3-d] [1,3]oxazine-2,4- dione 8oxide using 1,7-dimethyl-lH,4H-pyrido[2,3-d]

[1,3 oxazine-2,4-dione.

Example 77 7-Methyl-1-n-propyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4 dione8 oxide using 7-methyl-1-n-propyl- 1H,4H-pyrido [2,3-d][1,3]oxazine-2,4-dione.

Example 78 l-Isobutyl 7 methyl-1H,4H-pyrido[2,3-d][1,31oxazinc 2,4dione-8-oxide using l-isobutyl 7 methyl- 1H,4H-pyrido [2,3-d] [1,3oxazine-2,4-dione.

Example 79 Example 80 7-Acetoxymethyl 1 methyl-1H,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione using 1,7-dimethyl 1H,4H pyrido- [2,3-d][1,31oxazine-2,4-dione-8-oxide and acetic anhydride.

Example 81 7-Acetoxymethyl-l-n-propyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4-dione using 7-methyl1-n-propyl-1H,4H- pyrido[2,3-d][1,3]oxazine 2,4 dione-S-oxide and acetic anhydride.

Example 82 7-Acetoxymethyl 1 isobutyl-1H,4H-pyrido [2,3-d] [1,3]oxazine-2,4-dione using l-isobutyl 7 methyl-1H, 4H pyrido[2,3-d][1,3]oxazine 2,4 dione-8-oxide and acetic anhydride.

Example 83 7 Acetoxymethyl-l-n-hexyl-lH,4H-pyrido[2,3-d] [1,3]oxazine-2,4-dione using l-n-hexyl-7-methyl-1H,4H-pyrid0- [2,3-d][1,3]oxazine-2,4-dione-8-oxide and acetic anhydride.

Example 84 l-Ethyl 7 propionoxymethyl-1H,4H-pyrido[2,3-d] [1,3]oxazine2,4 dione using 1-ethyl-7-methyl-1H,4H- pyrido[2,3-d] [1,3]oxazine 2,4dione-8-oxide and propionic anhydride.

Example 85 l-Ethyl 7 isobutyroxymethyl-1H,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione using l-ethyl 7 methy1-1H,4H- pyrido[2,3-d][1,3]oxazine-2,4-dione-8-oxide and isobutyric anhydride.

Example 86 l-Ethyl 7 hexanoyloxymethyl-1H,4H-pyrido[2,3-d][1,3]oxazine-2,4-dione using l-ethyl 7 methyl-1H,4H pyrido [2,3-d]1,3]oxazine-2,4-dione-8-oxide and hexanoic acid anhydride.

Following the procedure described in Example 4 but using in place of1-ethyl-7-methyl-1H,4H-pyrido[2,3-d] [1,3]oxazine-2,4-dione a molarequivalent quantity of the appropriatel-(lower-alkyl)-7-(lower-alkanoyloxymethyl) 1 (lower-alkyl) 1H,4Hpyrido[2,3-d][1,3] oxazine-2,4-dione and either ethyl acetoacetate or amo lar equivalent quantity of ethyl formylacetate, there are obtainedthe corresponding l-(lower-alkyl)-l,4-dihydro- 7-hydroxymethyl 2methyl(or unsubstituted)-4-oxo- 1,8-naphthyridine 3 carboxylic acids ofExamples 87- 94 after alkaline hydrolysis as in Example 4 of thecorresponding ethyl 7-(lower-alkanoyloxy) 1 (lower-alkyl)1,4-dihydro-2-rnethyl(or unsubstituted)-4-oxo-1,8-naphthyridine-3-carboxylates first formed.

Example 87 1 Ethyl 1,4 dihydro-7-hydroxymethyl-4-oxo-1,8-naphthyridine-3-carboxylic acid using 7-acetoxymethyl-1- ethyl 1H,4Hpyrido[2,3-d] [1,3]oxazine-2,4-dione and ethyl formylacetate, andhydrolyzing the resulting ethyl 7-acetoxy-methyl 1ethyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate.

Example 88 1,4-Dihydro 7 hydroxymethyl-1-methyl-4-oxo-1,8- naphthyridine3 carboxylic acid using 7-acetoxymethyll-methyl 1H,4Hpyrido[2,3-d][1,3]oxazine-2,4-dione and ethyl formylacetate, andhydrolyzing the resulting ethyl 7-acetoxymethyl 1,4dihydro-4-oxo-l-n-propyl- 1,S-naphthyridine-3-carboxylate.

Example 89 1','4-Dihydro 7 hydroxymethyl-l-isobutyl-Z-methyl- 4-0xo 1,8naphthyridine-3-carboxylic acid using 7- acetoxymethyl 1isobutyl-1H,4H-pyrido[2,3-d][1,3] oxazine-2,4-dione and ethylacetoacetate, and hydrolyzing the resulting ethyl7-acetoxymethyl-1,4-dihydr0-l-isobutyl-2-methyl-4-oxo-1,8-naphthyridine-3-carboxylatc.

Example 90 l-n-Hexyl 1,4 dihydro-7-hydroxymethyl-2-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid using7-acetoxyrnethyl-l-n-hexyl-1H,4H-pyrido[2,3-d] 1,3 oxazine 2,4- dioneand ethyl acetoacetate, and hydrolyzing the resulting ethyl7-acetoxymethyl-l-n-hexyl-1,4-dihydro-2-methyl-4-oxo-1,8-naphthyridine-3-carboxylate.

Example 91 1 Ethyl 1,4 dihydro-7-hydroxymethyl-4-oxo-1,8- naphthyridine3 carboxylic acid using 1-ethyl-7-propionoxymethyl 1H,4H pyrido[2,3-d][1,3]oxazine-2,4- dione and ethyl formylacetate, and hydrolyzing theresulting ethyl l-ethyl-l,4-dihydro-4-oxo 7propionoxymethyl-1,8-naphthyridine-3-carboxylate.

Example 92 1 Ethyl 1,4 clihydro-7-hydroxymethyl-4-oxo-1,8- naphthyridine3 carboxylic acid using 1-ethyl-7-iso- 15 butyroxymethyl 1H,4Hpyrido[2,3-d] [1,3]oxazine-2,4- dione and ethyl formylacetate, andhydrolyzing the resulting ethyll-ethyl-1,4-dihydro-7-is0butyroxymethil-4-oxo-1,8-naphthyridine-3-carboxylate.

Example 93 l-Ethyl-1,4-dihydro-7-hydroxymethyl-2-methyl-4 oxo-1,8-naphthyridine-3-carboxylic acid using1-ethyl-7-hexanoyloxymethyl-1H,4H-pyrido[2,3 d] [l,3]oxazine 2,4- dioneand ethyl acetoacetate, and hydrolyzing the resulting ethyl1-ethyl-7-hexanoyloxymethyl 1,4 dihydro-2-methyl-4-oxo-1,8-naphthyridine-3-carboxylate.

We claim:

1. l-(Lower-alkyl) 7 Q-1H,4H-pyrido[2,3-d][1,3] oxazine-2,4-dione whereQ is lower-alkyl, lower-alkanoyloxymethyl, 4(or 3)-pyridyl or 4(or3)-pyridyl having one or two non-tertiary lower-alkyl substituents,where loweralkyl in each case has from one to six carbon atoms.

2. l-Ethyl 7 methyl 1H,4H pyrido[2,3-d][l,3] oxazine-2,4-dione accordingto Claim 1 where l-(loweralkyl) is l-ethyl and Q is methyl.

3. The process which comprises reacting 1-R -7-Q-1H, 4H-pyrido[2,3-d][1,310xazine 2,4 dione with a compound of the formula,

nr-i s-om-coon,

to produce a lower-alkyl 1-R -1,4-dihydro-2-R -7 Q 4-oxo-1,8-naphthyridine3-carboxylate of the formula 0 l{COOR R Q N I 2where R and R are each lower-alkyl, R is hydrogen or methyl, and Q islower-alkyl, lower-alkanoyloxymethyl, 4- (or 3)-pyridyl or 4(or3)-pyridyl having one or two nontertiary lower-alkyl substituents, andhydrolyzing said lower-alkyl 1,8-naphthyridine 3 carboxylate to producethe corresponding 1 R -1,4-dihydro-2-R -7-Q-4-oxo-1,8-naphthyridine-B-carboxylic acid where R and R are defined as above and Qis lower-alkyl, hydroxymethyl, 4- (or 3)-pyridy1 or 4(or 3)-pyridylhaving one or two nontertiary lower-alkyl substituents, wherelower-alkyl in each case has from one to six carbon atoms.

4. The process according to Claim 3 where Q is methyl, R and R areethyl, and R is hydrogen.

5. The process for producing 1-(lower-alkyl)-7-Q"-1H, 4H-pyrido[2,3-d][1,3]oxazine-2,4-dione which comprises 16 heating2-(lower-alkylamino)-6-Q"-nicotinic acid with a lower-alkylchloroformate or phosgene, where Q" is lower-alkyl, 4(or 3)-pyridyl or4(or 3)-pyridyl having one or tWo non-tertiary lower-alkyl substituents,where lower-alkyl in each case has from one to six carbon atoms.

6. The process which comprises reacting from ambient to steam bathtemperature 1 R -7-methy1-1H,4H-pyrido [2,3-d] [l,3]oxazine-2,3-dionewith an oxidizing agent capable of selectively converting pyridines topyridine-N- oxides to produce the corresponding 1-R -7-methyl-lI-I, 4Hpyrido[2,3-d] [1,3]oxazine-2,3-dione-8-oxide and reacting said 8-oxidewith a lower-alkanoic acid anhydride to produce 1-R 7(lower-alkanoyloxymethyl)-1H,4H- pyrido [2,3-d] [l,3]oxazine-2,3-dione.

7. The process which comprises reacting 1-R -7-Q-1H,4H-pyrido[2,3-d][1,3]oxazine 2,4 dione with a compound of the formula,

to produce a lower-alkyl 1-R 1,4 dihydro2-R -7-Q-4-oxo-1,8-naphthyridine-3-carboxy1ate of the formula l COOR UNITED STATESPATENTS 6/1971 Lesher et a1. 260295.5 B 3/1972 Lesher et a1 260295.5 B

ALAN L. ROTMA'N, Primary Examiner US. Cl. X.R.

UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OF CORRECTION.

. PATENT NO. 3 83 120 DATED September 24, 1974 INVENTO I Andrew W. Zalayand Malcolm R. Bell It is certified that error appears in theabove-identified patent and that said Letters Patent are herebycorrected as shown below: U

Column 3, line 7, "346,180" should read 346,190

Column 4, line 30, "VI" should read VI Column 5, line 6, "oxzine" shouldread oxazine Signed and Scaled this Sixteenth D y f November 1976 [SEAL]Arrest;

RUTH MASON C. MARSHALL DANN Arresting Officer (ommissiuner nj'latentsand Trademarks

